Chronic myeloid leukemia (CML) was the first human neoplasm associated with a recurrent genetic aberration; the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosome 9 and 22, giving rise to the constitutively active tyrosine kinase BCR/ABL11. In CML, the Ph chromosome is believed to originate in a hematopoietic stem cell (HSC) as it clonally can be found both in malignant myeloid cells and non-malignant lymphoid cells2. The Ph chromosome is also found in a fraction of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). CML is comprised of heterogeneous cell types of various maturation stages that are maintained by a small number of cells, termed CML stem cells, sharing the capacity to self-renew with normal HSC3. It has been demonstrated that the CML stem cells are at least partially resistant to current treatments with tyrosine kinase inhibitors4,5, which despite clinical success show a suppressive rather than curative effect in this disorder. Thus, identifying a strategy to efficiently target CML stem cells is highly desirable to achieve a permanent cure of the disorder. Such a strategy would be to identify a target on CML stem cells that may provide novel means to eradicate the CML stem cells. Encouraging reports in this direction have been described in the related disorder acute myeloid leukemia (AML), where antibodies targeting CD123, CXCR4, CD44 or CD47 on AML stem cells show anti-leukemic effects in AML animal models6-9. Further, AML stem cell associated antigens such as CD96 and CLL-1 have been identified10,11, providing additional target candidates in this disorder. Intriguingly, despite being one of the most studied neoplasms of all time, referred to as a stem cell cancer disorder, no cell surface biomarker has so far been identified in CML that allows a prospective separation of CML stem cells from normal HSCs, both residing in the rare CD34+CD38− cell population12,13. Identification of such a biomarker would be instrumental in the characterization of the CML stem cell, but could also be used for novel treatment developments and for tracking therapeutic effects on primitive CML cells during treatment.
Accordingly, the present invention seeks to provide agents for use in the treatment and diagnosis of neoplastic hematologic disorders, such as CML. In addition, the invention seeks to provide agent for use in treatment and diagnosis of other neoplastic hematologic disorders, such as ALL, AML, Ph chromosome-negative myeloproliferative disorders (MPD), and myelodysplastic syndromes (MDS).